Biologics: The Brave New World of Medicine

Imagine this future: Treatment of disease has become individualized and patient-specific. After assessing your genetic code, specialists design a unique treatment for you that modifies your genes to ward off any “problem” before it develops, and should something come up that was not initially detected, a corrective treatment is easily concocted. Sound far off? Maybe not that far…

Ancient Medicines

Chinese scholar-emperor, Shen Nung, who lived around 4,730 years ago, compiled a book about herbs that is the oldest record of medicine known.

Pliny the Younger, who was a lawyer, an author and a natural philosopher of Ancient Rome, living 2,000 years ago said, “Medicine changes every day, and we are swept along on the puffs of clever brains… as if thousands of people do not live without physicians – though not, of course, without medicine.”

The term Pharmacology – from the Greek: pharmacon (φάρμακον) meaning drug, and logos (λόγος) meaning science – is the study of how chemical substances interact with living systems. Substances are considered “pharmaceuticals” if they have medicinal properties. The credit for first recording information in pharmacopoeias goes to Arab physicians in Baghdad 800-1,250 years ago.

Modern, Conventional Medicine

Today, we have far more medicinal options than our ancestors, even those of only a generation or two ago, and our offspring will have access to treatments we only dream about. Scientists are approaching the multitude of human diseases from all angles and even though there have been some disasters along the way – such as when thalidomide damaged 15,000 fetuses throughout the world during the late fifties and early sixties – used appropriately, medicines still do much more good than harm. Medicines are one of the most useful and cost-effective tools in healthcare today.

A drug is any chemical substance other than a food or device that affects the function of living things. Physicians prescribe drugs to treat illness and some people use drugs recreationally to alter behaviour and perception. Caffeine is the most widely used psychoactive substance in the world.

Of all the medicines we have today, none exist that work 100% of the time for everyone and without side effects. Medicine is a bit like when Abraham Lincoln said, “You can fool some of the people all of the time, and all of the people some of the time, but you cannot fool all of the people all of the time.” There are great discoveries and wonderful medicines in our cabinets but disease and illness still abound. Medicines don’t work for all the people all the time because we’re different from each other. The quest for better and more specific medicines continues.

Usually created by combining chemicals, most conventional drugs generally have a short duration of action, necessitating ongoing daily dosing, using tablets taken orally. The chemical structures and formulas of conventional medicines define them as small molecule drugs. The underlying problem with using these conventional small molecule drugs is that they could affect various parts of the entire body in an undesired, non-specific way, leading to unwanted side effects. They work directly on the body and involve multiple sites, usually influencing a number of human systems.

The study of medicinal chemicals requires intimate knowledge of the biological system affected. With increasing knowledge of cell biology and biochemistry, the field of pharmacology has also changed substantially.

Since the mapping of the human genome in 2000, scientists are uncovering more disease-specific markers. Soon, it may be possible to create complete genetic profiles of individuals, identifying those with a known genetic susceptibility to inflammatory bowel disease, cancer, diabetes, osteoporosis, liver disease, heart disease – or perhaps any unwanted health condition. With this knowledge, professionals could counsel individuals to structure their diet and lifestyle to ward off disease onset – where possible – and drugs specific to the individual, not the disease, would not be far behind.

Biotechnology Influences Medicine

When Hungarian engineer Karl Ereky coined the word biotechnology in 1919 to describe the production of goods from raw materials with the aid of living organisms, he was describing techniques that human beings have been employing through the ages, such as selective breeding, fermentation, and hybridization. The Mesopotamian people used selective breeding, or artificial selection practices, to improve livestock as far back in recorded history as 8,000 years ago. Brewing beer, fermenting wine, and baking bread with help of yeast were all in practice 6,000 years ago, and the Chinese made yogurt and cheese using bacteria at least 4,000 years ago.

At the heart of the biotechnology revolution is genomics – the study of how genes interact with each other and their environment to make living organisms do what they do. New knowledge about the basic building blocks of life is touching all area of our lives, including food supply, industry, energy, and healthcare. In short, biotechnology is the manipulation of organisms to do practical things and to provide useful products.

Biotechnology has evolved to include modern techniques with new applications. The current highly developed state of biotechnology encompasses techniques such as genetic engineering (recombinant DNA technology), tissue culture, and others. These modern techniques also take considerably less time to produce desired changes in living organisms and carry greater precision than traditional techniques or medicines.

Canada’s biotechnology sector has expanded rapidly in the last decade, seeing a doubling in the number of core biotechnology companies to the current 454 in operation, and placing Canada second of all countries in the world (only behind the US) with the most biotech companies. Biotechnology is not limited to medicine, but includes industrial biotech and bioproduct, for example, biofuels such as ethanol produced from corn; waste that is turned into an energy source; and plants that change colour in the presence of TNT to detect land mines. Canadian scientists are also turning oilseeds into biodegradable polymers to produce bioplastics, which are plastics made from chemicals derived from agricultural products rather than fossil fuels.

A Canadian Biotechnology Index

The federal government spent $791 million on biotechnology in the fiscal year 2004/05, up 6.3% from $744 million the previous year.
Spending on biotechnology represented 9% of all federal spending on science and technology in 2004/05.
Virtually all (96 %) biotechnology spending was devoted to research and development.
Two-thirds (67%) of biotechnology science and technology activities were performed outside the federal government. The largest recipient was the higher education sector, which received $403 million – just over half of the total.
There were 1,656 fulltime equivalent person-years devoted to biotechnology science and technology activities in the federal government in 2004/2005, down from 1,727 during 2003/04.

Source: Statistics Canada

Medicines derived from Biotechnology

Canadians have been using biologics in a rudimentary form for more than two hundred years. The medical application of biotechnology has evolved from rudimentary vaccines to hormones to the state-of-the-art targeted biologics used today. Early use of biologic medicine emerged in 1796 with the creation of the very first vaccine, for smallpox, by British physician Edward Jenner. In this case, he gave non-infected people active cowpox virus, hoping to build their immunity against the related but deadly smallpox virus.

Drug manufacturers create vaccines from several sources: living, weakened strains of viruses or bacteria; killed or inactivated organisms, or purified products derived from them. These products intentionally give rise to trivial infections in the inoculated that sometimes are not even apparent, and produce resistance to future full-blown infection for those vaccinated individuals.

Another important and widely used biologic medicine came from Canada in 1921, when Drs. Banting and Best extracted the hormone insulin from pigs for use in humans to treat diabetes. Dr. Banting went on to share the Noble prize in medicine for this discovery.

Targeted biologic drugs differ from conventional drugs. The majority of conventional medications are chemical compounds that modify the way the body or mind works. In contrast, scientists derive biologic drugs from living organisms (e.g. human, animal, viral, and bacterial). Manufacturers create biologic protein medicines from living cell systems. These are intended to act in certain ways in the body to correct malfunctions – which may lead to disease – and block disease early in development.

Canadians on Biotechnology

More than 70% of Canadians agree that, “Biotechnology research represents the next frontier that will lead to significant quality of life benefits for all Canadians.”
About 80% of Canadians agree that, “We have to accept some risk to achieve the benefits of biotechnology, like new discoveries and cure of serious illness.”
A smaller majority, 63%, agree that, “Some risk is acceptable to achieve the benefits of biotechnology when applied to new foods that contain vitamins or medicine.”
Almost 90% of Canadians agree that, “Although there may be some unknown risks, technologies like biotechnology are part of the future, so all we can do is make sure that its uses are as safe as possible.”

The Conference Board of Canada, Biotechnology in Canada: A Technology Platform for Growth, October 2005.

What is even more interesting is how scientists formulate these new drugs. Biologic agents have large and complex structures. These protein molecules are so complex to construct that using living cell systems is the only way to manufacture them. The resulting molecules go through a complex purification process, transforming them into a form that is suitable for human use. Since they are proteins, the customary oral route for administering the medicine is usually not appropriate because the body would digest them, just like other sources of protein gained from the diet. Biologics are therefore taken by injection, subcutaneously (under the skin), intravenously (directly into a vein), or intramuscularly, and have a longer duration of action than conventional medicines.

New, state-of-the-art technology is permitting the manufacture of tailor-made molecules to mimic human biologically active proteins. These biologics act by blocking certain disease-causing messengers in the body and by blocking the disease process itself. Scientific advances have identified key molecular drivers of disease and researchers have discovered that some autoimmune diseases have common underlying mechanisms. Since various diseases have a common causative agent, a single biologic drug can successfully treat multiple diseases.

Due to their complex manufacturing process, biologic medications are more expensive than traditional drugs, and therefore physicians tend to use them as a “last resort.” This means that they become an option only for those patients who:

have not responded to conventional treatment,
have had harmful effects from conventional treatments,
are not able to take conventional treatments due to the risk that the expected side effects may pose to them, or
have signs that their disease will follow a very aggressive course.

Anti-Inflammatory Biologics

Inflammatory bowel disease (Crohn’s disease and ulcerative colitis), affecting about 180,000 Canadians, is one gastrointestinal condition that has greatly benefited from the discovery of the new biologic agents. Diseases like rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) begin in the immune system when something triggers certain cells to become active and to continue activity when they should have stopped. These overactive cells set off a series of events in the body. Inflammation is also the body’s reaction to injury and is a necessary process for the repair of injury. Tumour necrosis factor alpha (TNF-α) is a protein that the body produces too much of, leading to inflammatory disease.

Remicade® (infliximab), Enbrel® (etanercept), and Humira® (adalimumab), three different brands of medication within the same class, biological response modifiers, are protein products that block the inflammatory effects of tumour necrosis factor alpha (TNF-α). This class of medication as a whole is effective at reducing inflammation but it is important to remember the individual side of medicine – what works for one does not necessarily work for another. This is why it is so important for researchers to keep developing medicines, even when similar drugs already exist.

All three of these medications are available to treat rheumatoid arthritis patients. However, only Remicade® has indications in Canada for use in inflammatory bowel disease – for Crohn’s disease since 2001 and just recently for ulcerative colitis.

Interestingly, clinical trials using Enbrel® have not shown promise for inflammatory bowel disease.

Recent clinical trials for Humira®, released May 2006 at the Digestive Disease Week meeting in Los Angeles, found that 40-47% of patients randomized to Humira® (dosed every-other-week or weekly) were in remission at 26 weeks and 90% of these patients were still in remission at 56 weeks. One-third of the patients taking Humira® discontinued the use of steroids and remained in remission. A 2005 study found that 11/13 of the Crohn’s patients who had experienced a reduced, or loss of, response to Remicade® experienced a reduction in disease activity with Humira®. This promising evidence of success in treating Crohn’s disease might mean that this self-injected product could also become available in Canada to treat IBD in the future.

Having more than one medication in the same class is a good thing because if a patient with Crohn’s disease stops responding to one biologic response modifier, then all hope is not lost, as switching to another biologic medication might be just the trick to keep his or her symptoms at bay.

These products work by binding to TNF-α, preventing it from activating TNF receptors; thereby reducing the inflammatory response and its consequences. Adalimumab is constructed from a fully human monoclonal antibody, while infliximab is a mouse-human chimeric antibody and etanercept is a TNF receptor-IgG fusion protein. TNF-α inactivation has proven to be important in down-regulating the inflammatory reactions associated with autoimmune diseases.

The Future

It is there for us, somewhere just out of reach, that perfect medicine for everyone. We must hold on to current therapies as we take baby steps toward a disease-free human race. There are many more biologics under study for gastrointestinal and other diseases, which may help us to battle conditions that today have no treatment. Development of drugs, including biologics, takes time, and the pursuit of medicine through biotechnology is an ongoing, determined process. Alex Azar, the Deputy Secretary of the US Health & Human Services, stated in February 2006, “The vaccine, drug, and device industries are not floodlights that can be switched on when you hear a noise outside.” We need to nurture our scientists and encourage them to keep looking out for our best interests.

More than 8,000 years have passed since the Mesopotamian people improved their livestock with artificial selection practices and it may take us a long time to reach “instant” patient-specific medications, or the breakthrough could be just around the corner. Biotechnology scientists are like the scouts of old, who used to go out and see what was just ahead, keeping us informed of what is coming. Keep your eyes on the biotechnology industry to get a glimpse of where medicine is heading. It could surprise you.